In 2013, we pursued studies that can be broken down into four sections. 1) HIV-specific B-cell responses and antibodies obtained from single-cell analyses of B cells and B-cell subsets isolated from the peripheral blood of HIV-infected individuals;2) plasmablasts in the peripheral blood of HIV-infected individuals at different stages of disease;3) plasma cells in gut mucosal tissues in the presence and absence of gastrointestinal inflammation;and 4) B-cell features and functions in non-HIV immunodeficiencies. First, in a study almost completed with a manuscript in preparation, we have used new approaches involving flow cytometry and HIV envelope probes designed to investigate HIV-specific B cells in the peripheral blood of HIV-infected individuals at different stages of disease. We found that HIV-specific B-cell responses arise early after infection and are blunted by antiretroviral therapy and chronic HIV viremia. Furthermore, we used combinations of envelope probes with mutations in the CD4 and coreceptor (CoR) binding sites (bs) to show that the B cells directed against the CoRbs predominate over those against the CD4bs;yet, it is the latter specificity that has more neutralizing potential. In these multiparameter flow cytometric-based assays, we also included markers that can identify B-cell subsets circulating in the peripheral blood. Our findings show that HIV-specific responses are enriched within abnormal B-cell subsets, namely activated and tissue-like memory B cells that are largely absent in healthy donors. These findings suggest that it may prove difficult to elicit antibodies in uninfected individuals from a vaccine designed to recapitulate responses observed in infected individuals. However, our findings also show that the HIV-specific B-cell response in individuals who maintain low levels of HIV plasma viremia and immune activation is enriched within the resting memory B cells, the predominant subset in uninfected individuals. Finally, we have used single-cell cloning strategies to express IgG antibodies derived from two memory B cell subsets that circulate in the peripheral blood of chronically HIV-infected viremic individuals: the abnormal tissue-like memory B cells responsible for HIV-associated B-cell exhaustion and their normal resting memory B-cell counterparts. Preliminary indications are that IgG antibodies derived from the tissue-like memory B-cell compartment, display lower levels of somatic hypermutation and HIV neutralization potential as well as higher levels of polyreactivity and autoreactivity than those derived from their corresponding resting memory B-cell compartment. These findings suggest that HIV-induced B cell exhaustion is associated with the generation of ineffective antibodies, which in turn, may help explain why the antibody response in HIV-infected individuals does little to control disease progression. Second, in a study published in the Journal of Virology, we investigated plasmablasts that circulate in the peripheral blood of HIV-infected individuals at different stages of disease and of HIV-uninfected individuals. Plasmablasts represent less than 1% of B cells in the blood of healthy donors and, with the primary isotype being IgA, their origin is thought to be mucosal tissues. Following parenteral immunization there is a short-lived burst of plasmablasts in the blood, and in this case the primary isotype is IgG. These IgG+ plasmablasts are thought to originate from draining lymph nodes. In early HIV infection, plasmablasts were present at high frequencies in untreated individuals and while they were primarily IgA, a higher proportion of these plasmablasts were IgG+ when compared to HIV-uninfected individuals. In addition, the frequency of virus-specific plasmablasts in the blood of HIV-infected individuals was very low compared to other acute viral infections (dengue or influenza). In the chronic phase of infection, a higher than normal frequency of plasmablasts was maintained in untreated individuals and these were primarily of the IgG isotype, consistent with high serum IgG also observed in this group. The percentage of HIV-specific B cells did not increase during the chronic phase of HIV viremia, suggesting as others have, that plasmablasts in the blood of HIV-infected viremic individuals are primarily a consequence of polyclonal activation of B cells induced by ongoing viral replication. In this regard, we also found correlations between IgG levels and other soluble factors associated with HIV-induced immune activation. Thus, while the increased frequencies of IgG+ plasmablasts in the blood of HIV-viremic individuals may reflect gut perturbations (3rd section), they are more likely to be a reflection of systemic immune activation with involvement of other lymphoid tissues. Third, in a study completed with a manuscript submitted to the Journal of Allergy and Clinical Immunology, we characterized the plasma cells that reside in the gut (sigmoid colon) of patients with a history of colitis (chronic granulomatous disease (CGD) and Crohns disease (CD)), as well as chronically HIV-infected viremic and HIV-uninfected individuals. Gut mucosal inflammation has been described in HIV infection in the absence of a definitive cause and relatively little is known regarding the effects of such inflammatory processes on B cells. We found that CGD/CD-related colitis was associated with the presence of IgG+ plasma cells that expressed CXCR4 whereas the gut of healthy donors was primarily populated with plasma cells that expressed IgA and CCR10, the latter observation being consistent with reports in the literature. In chronically HIV-infected viremic individuals, we found an intermediate profile;while there was an increased frequency of IgG+ plasma cells in the gut when compared to healthy donors, the intensity of CXCR4 remained normal. Thus, our findings demonstrate that changes in the types of plasma cells that reside in the gut reflect a spectrum of inflammatory perturbations. Where there is gut inflammation in the absences of clinical manifestations, such as observed in HIV infection, there is skewing towards IgG+ plasma cells and where the tissue inflammation is accompanied by colitis, such as observed in CD and certain CGD patients, IgG+ plasma cells express high levels of CXCR4. Fourth, we have pursued several collaborative studies at NIAID and with other NIH institutes. In two studies, we pursued our longstanding interest in B-cell responses to influenza to investigate such responses following immunization in healthy individuals and in individuals with chronic granulomatous disease (CGD). CGD is an inherited immunodeficiency that is associated with low frequencies of classic memory B cells in the blood, similar to what has been reported in HIV-infected individuals. However, in contrast to reduced influenza-specific memory B-cell responses observed in HIV-infected individuals, the responses in the CGD group were not significantly different compared to age-matched healthy controls. These findings were published in Blood. The second influenza-based study, under review in Cell, was a large collaborative effort aimed at delineating the various facets of a healthy immune response with a systems biology approach. In a third collaborative effort with NIAID investigators that is under revision for the New England Journal of Medicine, we performed immunologic and virologic assays on B cells and T cells of two siblings with a loss of function mutation in the enzyme manosyl-oligosaccharide glucosidase, involved in N-linked protein glycosylation. In two other studies, both published in the Journal of Experimental Medicine, our group helped delineate human B-cell defects associated with mutations in the IL-21 receptor and in the scaffolding protein, CARD11.

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Dollery, Stephen J; Santiago-Crespo, Rey J; Kardava, Lela et al. (2014) Efficient infection of a human B cell line with cell-free Kaposi's sarcoma-associated herpesvirus. J Virol 88:1748-57
Sadat, Mohammed A; Moir, Susan; Chun, Tae-Wook et al. (2014) Glycosylation, hypogammaglobulinemia, and resistance to viral infections. N Engl J Med 370:1615-25
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Buckner, Clarisa M; Moir, Susan; Kardava, Lela et al. (2014) CXCR4/IgG-expressing plasma cells are associated with human gastrointestinal tissue inflammation. J Allergy Clin Immunol 133:1676-85.e5
Kardava, Lela; Moir, Susan; Shah, Naisha et al. (2014) Abnormal B cell memory subsets dominate HIV-specific responses in infected individuals. J Clin Invest 124:3252-62

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